Phenanthrene derivatives

ABSTRACT

PHENANTHRENE DERIVATIVES USEFUL AS MEDICAMENTS FOR ANTI-ANDROGENIC THERAPY AND ACNE-PROPHYLACTIC OR TREATMENT THEREOF.

United States Patent M ABSTRACT OF THE DISCLOSURE Phenanthrenederivatives useful as medicameuts for anti-androgenic therapy andacne-prophylactic or treatment thereof.

The present application is a divisional application of application Ser.No. 781,964, filed Dec. 6, 1968, now US. Pat. No. 3,661,999.

The present invention relates to a new group of highly potentanti-androgenic agents and more particularly to the compounds of thestructural formula:

wherein R and R each is a lower alkyl group; X is a member selected fromthe group consisting of hydrogen atom and a halogen atom; Y-Z is amember selected from the group consisting of CH -CH CH=CH, and

CHCH

and the dotted line indicates an optional 9,10 double bond.

As the substituents R and R in the above-cited General Formula I, alower alkyl group such as methyl, ethyl, propyl, i-propyl, butyl,i-butyl, pentyl, hexyl, or the like may be exemplified. Halogen atomsrepresented by the symbol X are fluorine and chlorine.

Representative of the compounds as defined by the General Formula I whenY-Z is CH CH are:

4ap-methyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren- 2-one,4a;3-ethyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren- 2-one,4afi-methyl-7-propoxy-2,3,4,4a-tetrahydrophenanthren 2-one,4afl-butyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren- 2-one,a-fluoro-4afl-methyl-7 methoxy-2,3 ,4,4a,9,IO-hexahydrophenanthren-Z-one, 1tlufluoro-4afl-ethyl-7-methoxy-2,3,4,4a,9,10-hexahydrophenanthren-2-one,1OB-chloro4afl-methyl-7-methoxy-2,3,4,4a,9,IO-hexahydrophenanthren-Z-one,10a-chloro-4aB-methyl-7-methoxy-2,3,4,4a,9,IO-hexahydrophenanthren-Z-one,10 8-chloro-4a,8-ethyl-7-methoxy-2,3,4,4a,9,10-hexahydrophenanthren-Z-one,10a-chloro-4a/3-ethyl-7-methoxy-2,3,4,4a,9,l0hexahydrophenanthren-Z-one,

3,798,272 Patented Mar. 19, 1974 10a-chloro-4a3-propyl-7-methoxy-2,3,4,4a,9,IO-hexahydrophenanthren-Z-one,10a-chloro-4ap-methyl-7-hexyloxy-2,3 ,4,4a,9,IO-hexahydrophenanthren-Z-one, 10fluoro-4aj3-methyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one,10-cfluoro4aB-ethyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one,1O-chlor0-4a/3-methyl-7-methoxy-2,3,4,4a-tetrahydropheuanthren-Z-one,lO-chloro4aB-ethyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one,10-chloro-4afl-penty1-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one,and 10-chloro4aB-methyl-7-propoxy-2,3,4,4a-tetrahydrophenanthren-Z-one.

Representative of the compounds as defined by the General Formula I whenY-Z is CH=CH are:

10-fluoro4aB-methyl-7-methoxy-2,4a-dihydrophenanthren-Z-one,10-fluoro-4a/3-ethyl-7-methoxy-2,4a-dihydrophenanthren-Z-one,10-chloro-4afl-methyl-7-methoxy-2Aa-dihydrophenanthren-Z-one,10-chloro-4ap-ethy1-7-methoxy-2,4a-dihydrophenanthren-Z-one,10-chloro4afl-isopropyl-7-methoxy-2,4a-dihydrophenanthren-Z-one,10-chloro-4afi-propyl-7-meth0xy-2,4a-dihydrophenauthren-Z-one,10-chloro-4ap-methyl-7-ethoxy-2,4a-dihydrophenanthren-2-one, and10-chloro-4a,8-ethyl-7-etl1oxy-2,4a-dihydrophenanthren-Z-one.

Representative of the compounds as defined by the General Formula I whenY--Z is are I 4afl-methyl-3 a,4a-methylene-7-methoxy-2,3 ,4,4a,9, 10-

hexahydrophenanthren-Z-one,

4aB-ethyl-3(1,4a-methylene-7-methoxy-2,3,4,4a,9,1O-

hexahydrophenanthren-Z-one,

4a/3-butyl-3 a,4a-methylene-7-methoxy-2,3 ,4,4a,9, 10-

hexahydrophenanthren-Z-one,

4afl-ethyl-3 a,4a-methylene-7-hexyloxy-2,3,4,4a,9,10

hexahydrophenanthren-Z-one,

4a/3-methyl-3nh-methylene-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one,

4afl-ethyl-3a,4a-methy1ene-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one,

4afl-propyl-3a,4u-methylene-7-methoxy-L3,4,4a-tetrahydrophenanthren-Z-one,

4ap-methyl-3a,4a-methylene-7-butoxy-2,3,4,4a-telrahydrophenanthren-Z-one,

10-fluoro-4afi-methyl-3 u,4a-methylene-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one,

10-fluoro-4ap-ethyl-3 m,4a-methylene-7-methoxy-2,3,4,4a-tetrahydrophenauthren-Z-one,

10-chloro-4aB-methyl-3 u,4a-methylene-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one,

1-0-chloro-4afl-ethyl-3 a,4a-methylene-7-methoxy.

2,3,4,4a-tetrahydrophenanthreu-2-one,

10-chloro-4afl-propyl-3 a,4a-methylene-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one, and

10-chloro-4afl-methyl-3 a,4u-methylene-7-pentyloxy-2,3,4,4a-tetrahydrophenanthren-Z-one.

The compounds of the General Formula I may be more specificallyindicated by the following structural formulae:

(VII) (VIII) wherein R and R each have the same meanings as describedabove; X represents fluorine or chlorine; and 2 means the substituent Xhas the ocor p-configuration.

All the compounds may be prepared from the wellknown compounds of thegeneral formula:

I OR

wherein R and R each has the same meanings as described above.

The compounds of the General Formula II can be prepared by ketalizingthe starting Compound IX to yield a ketal derivative of the GeneralFormula X, epoxidizing the latter with a peracid to yield an epoxyderivative of the General Formula XI, interacting the latter with ahydrogen halide (HX'; wherein X has the same meanings as describedabove) to yield a halohydrin of the General Formula XII, and thendehydrating the latter with a dehydrating agent to yield an objectiveCompound II.

wherein R and R each has the same meanings as described above; R and Rrepresent a lower alkyl group or, combined each other, ethylene ortriethylene group; and X has the same meanings as described above.

The ketal derivatives of the above Formula X are those of dimethylketal, diethyl ketal, dipropyl ketal, ethylene ketal, trimethyleneketal, and the like. The ketalization may be carried out as usual way byreacting the starting Compound IX with a corresponding alcohol (e.g.methanol, ethanol, propanol, ethylene glycol, trimethylene glycol etc.)in the presence of a catalyst (e.g. p-toluenesulfonic acid,borontrifluoride, selenium dioxide, perchloric acid, hydrogen chlorideetc.). In this reaction the double bond (1-10a) conjugated with thecarbonyl group at the 2-position may be shifted to the Bn-deconjugatedposition (l010a).

The epoxydation of the Compounds X to the Compounds X1 is achieved byreacting a Compound X with a peracid such as performic acid, peraceticacid, trifiuoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid,mor p-nitroperbenzoic acid, perphthalic acid, or the like in a suitablesolvent (e.g. benzene, chloroform, dichloromethane, dichloroethane,ether, tetrahydrofuran, dioxane, acetone, ethyl acetate etc.).

The halohydrin formation from the Compounds XI to the Compounds XII iscarried out by reacting an epoxide (XI) with a hydrogen halide (i.e.hydrgen fluoride, hydrogen chloride, or a salt thereof with pyridine) ina suitable solvent (e.g. chloroform, dichloromethane, dichloroethane,methanol, ethanol, ether, tetrahydrofuran, dioxane, acetone, water, or amixture thereof) at low temperature or room temperature.

The dehydration of the Compounds XII to the objective Compounds 11 isachieved by interacting a halohydrin (XII) with a dehydrating agent(e.g. thionyl chloride, phosphorus oxychloride, phosphorus trichloride,phosphorus pentachloride, phosphorus tribromide, hydrogen chloride,hydrochloric acid, sulfuric acid, an arylsulfonic acid, phosphoruspentoxide, acetic anhydride, sodium bisulfite, potassium bisulfite,sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassiumcarbonate, an inorganic acid chloride, an anhydrous inorganic salt,alumina, an aluminum salt etc.). The ,B-configuration of the halogenatom at the l0-position in the halohydrin (XII) may be sustained orinverted to the zit-configuration according to the reaction conditionused. For example, the dehydration with thionyl chloride sustains theB-configuration, and, on the other hand, the dehydration with hydrogenchloride affords the Compounds II possessing the tit-configuration,

The respective compounds of the General Formulae III and IV can beprepared by enolizing the starting compounds IX and the above-describedCompounds II to yield the enol derivatives of the General Formula XHI:

(XIII) wherein R, R, and X each has the same meanings as describedabove; and R represents a lower alkyl group, and then dehydrogenatingthe latter with a dehydrogenating agent of a quinone type.

The enolization of the Compounds IX and II is carried out according tothe reaction condition of enolization as usual, for example, byinteracting the Compounds IX and II with 2,2 dimethoxypropane ormethyl-, ethyl-, or propyl-orthoformate in a suitable solvent (e.g.methanol, ethanol, propanol, dioxane, benzene etc.) in the presence ofan acid catalyst (e.g. p-toluenesulfonic acid, sulfuric acid etc.) toyield the corresponding methyland propylenol ethers (XIII).

The dehydrogenation of the enol derivatives (XIII) is achieved by adehydrogenating agent of a quinone type. In the present invention, DDQ(2,3-dichloro-5,6-dicyano- 1,4-benzoquinone) is preferably used as 'adehydrogenating agent of a quinone-type. The solvents used are dioxane,tetrahydrofuran, benzene, toluene, t-butanol, acetic acid, ethylacetate, trichloroethylene, and a mixture thereof, and more preferablesolvent is aqueous acetone containing a small amount of water. Thereaction proceeds very well at room temperature or low temperature, andmoreover it is proper to use an acid catalyst such as ptoluenesulfonicacid, trichloroacetic acid, p-nitrophenol, picric acid, maleic acid,oxalic acid, 3,5-dinitrobenzoic acid, or the like. Besides theabove-cited DDQ, as dehydrogenating agent of a quinone type in thepresent invention, tetrachloro-1,4 benzoquinone (chloranil),2,3-dibenzoyl-1,4-benzoquinone, or the like may be used.

The compounds of the General Formula V can be prepared from theabove-described Compounds IV by the selective dehydrogeneration. In thepresent invention, the selective introduction of the double bond at the3-4 position may be carried out according to the dehydrogenation methodfor the preparation of A -3-ketosteroids or terpenoids, for example, themethod by selenium dioxide or a derivative thereof (e.g.dibenzoyloxyselenoxide) e.g. H. J. Ringold et al., I; Am. Chem. Soc.,81, 5991 (1959)) or a quinone-type dehydrogenating agent such as DDQ,chloranil, fluoranil, 2,3,5,6-tetracyano-1,4-benzoquinone,2,3-dicyano-1,4-benzoquinone, 2,3 dibromo-6,6-dicyano- 1,4-benzoquinone,or the like (e.g. D. Walker and J. D. Hiebert, Chem. Rev., 67, 153(1967)).

The reaction, for example in the case of the reaction by seleniumdioxide, may be carried out by heating under stirring a solution of thestarting compound and selenium dioxide in a solvent such as an alcohol(e.g. t-butanol, tamyl alcohol etc.) or a lower fatty acid (e.g. aceticacid etc.) or a mixture thereof, if necessary, adding pyridine. Thereaction by DDQ may be carried out in a solvent such as dioxane,tetrahydrofuran, benzene, t-butanol, or the like, and the reaction bychloranil may be carried out in a lower alcohol such as t-butanol,s-amyl alcohol, or the like, under heating in any case. This reactioncondition may be applied to the formation of the compounds of theGeneral Formula XIV:

(XIV) ring can be prepared by adding a methylene group into an olefin bymeans of the some reaction methods such as formation and addition of theso-called carbene or addition of a carbenoid reagent, e.g. Simmons-Smithreaction (H. E. Simmons and R. D. Smith, I Am. Chem. Soc., 80, 5323(1958)). In the present invention, the cyclopropane formation maypreferably be accomplished by reacting a double bond with diazomethane(R. Wiechert and E. Kaspar, Chem. Ber., 93, 1710 (1960)) or by reactingwith dimethylsulfoxonium methylide (E. J. Corey and M. Chaykovsky, I.Am. Chem. Soc., 87, 1353 (1965); G. W. Krakower and H. Ann Van Dine, J.Org. Chem., 31, 3467 (1966) General procedure by reaction withdiazomethane consists in dissolving the above-described Compounds )GV orV in a' diazomethane-ether solution and keeping at room temperature orlow temperature for several minutes or several days. This affordsintermediately a pyrazoline derivative of the General Formula XV:

wherein R, R, X, and the dotted line each has the same meanings asdescribed above. In this reaction a suitable aprotic solvent asco-solvent such as benzene, toluene, dioxane, tetrahydrofuran,chloroform, dichloromethane, carbon tetrachloride, hexane, or the likemay be used under consideration of solubility of the starting materials.Thus resultant pyrazoline derivative (XV) is then converted into theobjective cyclopropanophenanthrene Compounds VI, VII, and VIII by acidor thermal decomposition. Acid decomposition may :be carried out bykeeping the intermediate (XV) at room temperature in a suitable inertsolvent in the presence of perchloric acid or boron trifluoride-ethercomplex. This reaction proceeds being accompanied by evolution ofnitrogen gas. Thermal decomposition may be carried out by heating thepyrazoline intermediate (XV) without any solvent or in a suitable highlyboiling solvent.

The reaction utilizing dimethylsulfoxonium methylide may be carried outby dissolving the starting Compounds XIV or V in dimethylsulfoxoniummethylide-dimethylsulfoxide solution and then keeping at roomtemperature for several hours or several days with stirring.

The novel compounds of the present invention respectively exhibit highlypotent anti-androgenic, anti-myogenic and anti-thymolitic activitieswithout any other hormonal activity and therefore they are useful asmedicaments for anti-androgenic therapy such as hirsutism, prostatauxe,prostatelcosis, prostatalgia, prostatism, or precocious diseases. Thecompounds are further useful for prophylactic and therapy against acne,especially acne vulgaris of sebaceous type since they exhibitcontrolling eifect to excess secretion from the sebaceous glands.

When the compounds of the present invention are employed as medicamentsfor anti-androgenic therapy they may be administered alone or incombination with pharmaceutically acceptable carriers, the proportion ofwhich is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard pharmaceuticalpractice. For example, they may be orally administered in single ordivided doses containing from 0.l mg. of the active ingredient in theform of tablets or capsules for oral administration. They may also beinjected parenterally, that is intramuscularly, intravenously orsubcutaneously, in the form of a sterile solution containing other perse conventional solutes.

When the compounds of the present invention are employed forprophylacetic or therapy against acne they may be administered insolution or ointment in suitable vehicles containing from 0.01-% of theactive ingredient. The invention will be better explained by thefollowing examples which are not intended as a limitation thereof. Alltemperatures stated are in degrees centigrade C.)

EXAMPLE 1 B-chloro-4afi-methyl-7-methoxy-2, 3 ,4,4a,9, 10-hexahydrophenanthren-Z-one A mixture of 22.5 g. of4aB-methyl-7-methoxy-2,3,4, 4a,9,10-hexahydrophenanthren-2-one, 0.9 g.of p-toluenesulfonic acid, 25. ml. of ethylene glycol, and 840 ml. ofanhydrous benzene is refluxed for hours with separation of water byazeotropic distillation. The reaction mixture is poured into ice-cooled2 N-sodium carbonate solution and extracted with ether. The etherextract is washed with water, dried over anhydrous sodium sulfate, andevaporated to dryness to yield crude crystals, which onrecrystallization from dichloromethane-ether afford 22.6 g. of the ketalderivative, 2,2-ethylenedioxy-4afimethyl-7-methoxy 1,2,3,4,4a,9hexahydrophenanthren- 2-one, having M.P. 121-123 C.

Analysis.-Calcd. for C H O (percent): C, 75.49; H, 7.74. Found(percent): C, 75.47; H, 7.71.

To a solution of 22.25 g. of the above resultant ketal derivative in 150ml. of a dichloromethane is added dropwise a solution of 18.7 g. ofm-chloroperbenzoic acid (82% purity) in 280 ml. of dichloromethane at0-2 C. under stirring over a period of minutes. The reaction mixture isstirred at the same temperature for 30 minutes and then at roomtemperature for 3.5 hours. Then, the reaction mixture is poured intoice-cooled 2 N- sodium carbonate solution and the organic layer isseparated. The aqueous layer is further extracted with dichloromethaneand the combined organic layer is washed with 1 N-sodium carbonatesolution and then with water, dried over anhydrous sodium sulfate, andevaporated to dryness to yield a crystalline material, which onrecrystallization from dichloromethane-acetone affords 13.08 g. of thea-epoxy derivative, 10a,l0a-epoxy-2,2-ethylenedioxy-4aB-methyl 7methoxy-1,2,3,4,4a,9,10,10a-octahydrophenanthren-Z-one, having M.P.195-196 C.

IR: 7 9 55 1614, 1582,1504, 1098, 1073 cm:

AnalysiS.Calcd. for C H O (percent): C, 71.50; H, 7.33. Found (percent):C, 71.44; H, 7.36.

The mother liquid on chromatography over alumina alfords 8.07 g. of thefl-epoxy derivative, 10,8,10a/3-epoxy- 2,2ethylenedioxy-4a18-methyl-7-methoxy-1,2,3,4,4a,9,10, 10aoctahydrophenanthren 2 one, having M.P. 130- 131 C.

To a solution of 9.75 g. of the above resultant a-epoxy derivative in300 ml. of tetrahydrofuran is added dropwise 18 ml. of cone.hydrochloric acid at 10 C. under stirring. The reaction mixture is keptat 01 C. for 2 hours under continuous stirring, poured into ice-cooled 2N-sodium bicarbonate solution, and then extracted with dichloromethane.The extract is washed with water, dried over anhydrous sodium sulfate,and evaporated to dryness. The resulting crystalline residue iscrystallized from dichloromethane-ether to afford 8.25 g. of thechlorohydrin derivative, l0fi-chloro-4afi-methyl 10am hydroxy-7-methoxy-1,2,3,4,4a,9,10,10a-octahydrophenanthren 2-one, having M.P.161-162" C.

max. cm.

of thionyl chloride under ice-cooling. After stirring for 5 minutes, thereaction mixture is poured into ice-water and extracted with ether. Theextract is washed with water, 2 N-hydrochloric acid, and then water,dried over anhydrous sodium sulfate, and evaporated to dryness. Theresulting crude crystals are recrystallized from ether-pentane to afford1.50 g. of10,9-chloro-4afl-methyl-7-methoxy-2,3,4,4a,9,10-hexahydrophenanthren-Z-one,having M.P. -126" C.

UV: 12,2 232 m,.( 23,200). IR: 7319 1674, 1616, 1580, 1503 010:

Analysis.Calcd. for C16H'1'1O2C1 (percent): C, 69.43; H, 6.19; Cl,12.81. Found (percent): C, 69.61; H, 6.20; Cl, 12.59.

EXAMPLE 2 1018-chloro-4afi-ethyl-7-methoxy-2,3,4,4a,9,10-hexahydrophenanthren-2-one A mixture of 30.0 g. of4afi-ethyl-7-methoxy-2,3,4,4a, 9,10-hexahydrophenanthren-2-one, 900 mg.of p-toluene- ,sulfonic acid, 21.8 g. of ethylene glycol, and 1500 ml.of anhydrous benzene is refluxed for 2 hours with separation of water byazeotropic distillation. After cooling, the reaction mixture is pouredinto aqueous sodium carbonate solution and the product is extracted withether. The ether extract is washed with water, dried over anhydroussodium sulfate, and evaporated to dryness to yield crude crystals, whichon recrystallization from methanol afford 32.5 g. of the ketalderivative, 4aB-ethyl- 2,2 ethylenedioxy-7-methoxy 1,2,3,4,4a,9hexahydrophenanthren-Z-One, having M.P. 107-108 C.

UV: 133 278, 286 m (6 1,830, 1,760). IR: 73 5,11 1615, 1589, 1504, 1243,1117, 1087, 104.4 6111- Analysis.-Calcd. for 0 11 0 (percent): C, 75.97;H, 8.05. Found (percent): C, 75.82; H, 8.19.

To a solution of 5.00 g. of the above resultant ketal derivative in 30ml. of dichloromethane is added drop Wise a solution of 3.72 g. ofm-chloroperbenzoic acid in 37 ml. of dichloromethane below 5 C. understirring over a period of 14 minutes. After completion of addition, thereaction mixture is further stirred at room temperature for 3 hours andthen poued into cooled 2 N- sodium carbonate solution. The product isextracted with ether, washed with water, dried over anhydrous sodiumsulfate, and evaporated to dryness-to yield crude crystals, which onrecrystallization from acetone-ether afford 4.88 g. of the a-epoxyderivative, 10a,10aa-epoxy-4a/3-ethyl- 2,2 ethylenedioxy 7methoxy-1,2,3,4,4a,9,10,10a-octahydrophenanthren-Z-one, having M.P.121-122 C.

UV: 393 276.5, 283.5 m1. (3 1,620, 1,510). IR: .33 1614, 1580, 1503,1128, 1098, 102 6111- Analysis.-Calcd. for C H O (percent): C, 72.12; H,7.65. Found (percent): C, 72.40; H, 7.83.

To a solution of 150 mg. of the above resultant aepoxy derivative in 5ml. of tetrahydrofuran is added 0.20 ml. of cone. hydrochloric acid at 5C. under stirring. The reaction mixture is kept at 05 C. for 3 hoursunder continuous stirring and then poured into cooled saturated sodiumbicarbonate solution, and the product is extracted with ether. Theextract is washed with water, dried over anhydrous sodium sulfate, andevaporated to dryness. The resulting residue is crystallized from etherto afford 89 mg. of the chlorohydrin derivative, 10 8-chloro 4a/3 ethyl10aa hydroxy-7- methoxy 1,2,3,4,4a,9,1-0,10a octahydrophenanthren-Z-one, having M.P. 135-l36 C.

IR; 7,9,3; 3550, 3336, 1730, 1613, 1580, 1501 cm.

Analysis.Calcd. for C H O Cl (percent): C, 66.12; H, 6.86; CI, 11.48.Found (percent): C, 65.74; H, 7.29; CI, 11.74.

To a solution of 3.299 g. of the above resultant chlorohydrin derivativein 26 ml. of anhydrous pyridine is added 1.3 ml. of thionyl chlorideunder ice-cooling. After stirring for 5 minutes, the reaction mixture ispoured into ice-water and extracted with ether. The ether extract iswashed with water, 2 N-hydrochloric acid, and then water, dried overanhydrous sodium sulfate, and evaporated to dryness. The resulting crudecrystals are recrystallized from ether-pentane to afford 1.833 g. of10,B-chloro-4aB-ethy1 7 methoxy-2,3,4,4a,9,10-hexahydrophenanthren-Z-onehaving M.P. 95.597 C.

UV: 1353 232, 244.5 1H,. (6 17,200, 14,500 IR: 15,213 1030, 1015, 1530,1501, 12 4, 104.3 cm."

Analysis.-Calcd. for C H O CI (percent): C, 70.21; H, 6.59 CI, 12.19.Found (percent): C, 70.38; H, 6.95; Cl, 12.44.

EXAMPLE 3 10a-chloro-4aB-methyl-7-methoxy-2,3,4,4a,9,10-hexahydrophenanthren-Z-one Gaseous hydrogen chloride is passed in asolution of 700 mg. of 10p-chloro-4a 8-methyl-l0aa-hydroxy-7- methoxy1,2,3,4,4a,9,10,10a octahydrophenanthren-2- one in 90 m1. of glacialacetic acid for 2 hours under water-cooling (about 10 C.) and stirring.After stopping the introduction of hydrogen chloride, the reactionmixture is further stirred at room temperature for 1 hour and thenpoured into ice-water. The product is extracted with dichloromethane,washed with water, dried over anhydrous sodium sulfate, and evaporatedto dryness to yield 647 mg. of crude crystals, which onrecrystallization from dichloromethane-ether afford 567 mg. of 10a.-chloro-4aB-mcthyl-7-methoxy 2,3,4,4a,9,10 hexahydrophenanthren-Z-onehaving M.P. 160-162 C.

UV: 1332 230 m). 23,700). IR: .33 1035, 1014, 1503, 1246, 876"cm.'

Analysis.-Calcd. for C H O Cl (percent): C, 69.43; H, 6.19; Cl, 12.81.Found (percent): C, 69.39; H, 6.23; CI, 13.3 6.

EXAMPLE 4 10 a-chloro-4afl-ethyl-7-methoxy-2,3,4,4a,9,10hexahydrophenanthren-Z-one According to the same procedure as Example 3,a solution of 725 mg. of 10B-chloro-4afl-ethyl-10ac -hydroxy-7- methoxy1,2,3,4,4a,9,l0,10a octahydrophenanthren-2- one in 90 ml. of glacialacetic acid is treated with gaseous hydrogen chloride. The resultingproduct is recrystallized from dichloromethane-ether to afford 420 mg.of 1011- chloro-4a 9-ethyl-7-methoxy-2,3,4,4a,9,10-hexahydrophenanthren-Z-one having M.P. 126127 C.

UV: A222? 231 Ill .1. (e 23,100)

Analysis. Calcd. for C H O CI (percent): C, 70.21; H, 6.59; C1, 12.19.Found (percent): C, 70.32; H, 6.57;

EXAMPLE 4afi-methyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one To asolution of 4.8 g. of 4afl-methyl-7-methoxy-2,3,4,4a,9,10-hexahydrophenanthren-2-one in 250 ml. of anhydrous benzene areadded 20 ml. of ethanol, 20 ml. of ethyl orthoformate, and 250 mg. ofp-toluenesulfonic acid hydrate, and the solution is kept at roomtemperature for 3 hours under nitrogen atmosphere. Then, the reactionmixture is poured into ice-water saturated with sodium bicarbonate andthe product is extracted with ether, washed with water, dried overanhydrous sodium sulfate, and evaporated to dryness under reduced pressure to yield 5.6 g. of the enol ether derivative, 2-ethoxy-4ap-methyl-7-methoxy-3,4,4a,9-tetrahydr0phenanthrene.

To a solution of this enol ether derivative in 320 ml. of acetone isadded a solution of 6.0 g. of DDQ in ml. of 95% acetone, and thesolution is kept at room temperature for 10 minutes under stirring. Thereaction mixture is poured into ice-water and the product is extractedwith ether, washed with 2 N-sodium carbonate solution and then water,dried over anhydrous sodium sulfate, and evaporated to dryness underreduced pressure to yield 5.31 g. of residue, which is passed through acolumn of 60 g. of alumina. Eluate with petroleum ether-benzene (1:l1:2)is crystallized from ether-pentane to afford 3.62 g. of4afl-methyl-7-methoxy-2,3,4,4atetrahydrophenanthren-Z-one having M.P.l08-109 C.

UV: X512? 215, 245, 265, 326, 366 my (6 18,900, 14,400, 8,830, 11,700,8,200)

Analysis.-Calcd. for 0 .01 0, (percent): C, 79.97; H, 6.71. Found(percent): C, 80.81; H, 6.78.

EXAMPLE 6 4afi-ethyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren- 2-one Abenzene solution of 20 g. of 4afl-ethyl-7-methoxy-2,3,4,9,10,lZ-hexahydrophenanthren-Z-one in 1 liter of anhydrous benzeneis dried by azeotropic distillation. The solution, to which are added 88ml. of ethanol, 88 ml. of ethyl orthoformate, and 1 g. of pyridinehydrochloride, is refluxed for 7 hours under nitrogen atmos phere. Aftercooling, the reaction mixture is poured into ice-cooled 2 N-sodiumcarbonate solution and the product is extracted with ether, washed withwater, dried over anhydrous sodium sulfate, and evaporated to drynessunder reduced pressure to yield 24.4 g. of the enol ether derivative,2-ethoxy-4a 8-ethyl-7-methoxy-3,4,4a,9 tetrahydrophenanthrene.

To a solution of this enol ether derivative in 1.3 liter of 95 acetoneis added a solution of 23.4 g. of DDQ in 700 ml. of 95 acetone, and thesolution is kept at room temperature for 10 minutes under stirring. Thereaction mixture is poured into ice-water and the product is extractedwith ether, washed with 2 N-sodium carbonate solution and then water,dried over anhydrous sodium sulfate, and evaporated to dryness underreduced pressure to yield 18.9 g. of residue, which on crystallizationfrom acetone-ether affords 15.79 g. of 4aB-ethy1-7-methoxy-2,3,4,4a-tetrahydrophenanthren-2-one having M.P. 86-87 C.

UV: 3351;? 248, 204.5, 327 m 13,500, 9,300, 3,300 IR: 13 2111005, 1003,1503, 1494, 1250, 1045 cm."

AnaIysis.-Calcd. for C H O (percent): C, 80.28; H, 7.13. Found(percent): C, 80.39; H, 7.15.

EXAMPLE 710-chloro-4a/3-methyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one Toa solution of 276 mg. of l0-chloro-4ap-methyl-7- methoxy 2,3,4,4a,9,10hexahydrophenanthren-Z-one in 22 m1. of anhydrous benzene are added 1.1ml. of anhydrous ethanol, 1.1 ml. of ethyl orthoformate, and 10 mg. ofp-toluenesulfonic acid, and the solution is kept at room temperature for2.5 hours under nitrogen atmosphere. Treatment according to the sameprocedure as Example 5 affords 320 mg. of the enol ether derivative,IO-chloro- 2ethoxy-4afi-methyl-7-methoxy-3,4,4a,9-tetrahydrophenanthrene.

To a solution of the enol ether derivative in 20 ml. of 95% acetone isadded a solution of 250 mg. of DDQ in 11 ml. of 95 acetone, and thesolution is kept at room temperature for 25 minutes under stirring. Theproduct obtained by treating according to the same procedure as Example5 is crystallized from ether-pentane to yield 235 11 mg. of10-chloro-4aB-methyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-onehaving M.P. 9798 C.

UV: 3553 216.5, 247.5, 270, 333.5, 374 my (3 23,300, 15,900, 10,300,11,900, 8,100). IR: 51 2846, 2826, 1674, 1614, 1603, 1584, 1562, 1501,1495, 1268, 1254 CHI-'- Analysis. Calcd. for C H O Cl: C, 69.94; H,5.50; CI, 12.91. Found: 0, 69.66; H, 5.57; 01, 13.12.

EXAMPLE 810-chloro-4afl-ethyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one To asolution of 1.47 g. of 10-chloro-4ap-ethyl-7-methoxy 2,3,4,4a,9,10hexahydrophenanthren-2-one in 150 ml. of anhydrous benzene are added 7ml. of anhydrous ethanol, 7 m1. of ethyl orthoformate, and 80 mg. ofp-toluenesulfonic acid-hydrate and the solution is kept at roomtemperature for 2 hours under nitrogen atmosphere. Treatment accordingto the same procedure as Example 5 afiords 2.36 g. of the enol etherderivative,chloro-2-ethoxy-4ap-ethyl-7-methoxy-3,4,4a,9-tetrahydrophenanthrene.

To a solution of the enol ether derivative in 100 ml. of 95% acetone isadded a solution of 1.35 g. of DDQ in 40 m1. of 95% acetone and thesolution is kept at room temperature for minutes under stirring. Theproduct obtained by treating as usual manner is passed through a columnof 30 g. of alumina and the elution with benzene affords 1.35 g. of 10chloro 4afl-ethyl-7-methoxy-2,3,4, 4a tetrahydrophenanthren 2 one havingB.P. 180 C./0.015 mm. Hg (bath temperature).

UV: A512? 249.5, 270 334, 378 mu (8 15,770, 10,450, 11,190, 8,250). IR:v gif 1675, 1614, 1603, 1563, 1499, 1268, 1254, 1040, 894 cm.

Analysis.--Calcd. for C H O CI (percent): C, 70.70; H, 5.93; C], 12.28.Found (percent): C, 70.13; H, 5.89; Cl, 12.15.

EXAMPLE 9 10-chloro-4a S-methy1-7-methoxy-2Aa-dihydrophenanthren-Z-oneTo a solution of 3.57 g. of 10-chloro-4a 3-methy1-7- methoxy2,3,4,4a,-tetrahydrophenanthren 2 one in 180 ml. of t-butanol are added0.58 ml. of anhydrous pyridine and 1.73 g. of selenium dioxide and thesolution is refluxed for 15.5 hours under nitrogen atmosphere. Aftercooling, the reaction mixture is poured into ice-water and the productis extracted with dichloromethane. The extract is washed with water,dried over anhydrous sodium sulfate, and evaporated to dryness underreduced pressure to aflord 3.8 g. of a reddish yellow oily material,which is chromatographed on a column of 125 g. of silica gel (Woelmgrade-H: containing 10% of water). Eluate with benzene orbenzene-chloroform (3:7) is recrystallized from dichloromethane-ether toyield 2.24 g. of 10-chloro- 4a 3 methyl 7 methoxy2,4a-dihydrophenanthren-2- one having M.P. 130131 C.

UV: 15,32? 230, 263, 335, 383 m, (6 21,660, 16,310, 9,090, 5,080). IR:9,2,3; 1664, 1629, 1603, 1563, 1498, 1481, 1265, 1258, 898, 890 cm.

Analysis.-Calcd. for C H O Cl (percent): C, 70.46; H, 4.80; Cl, 13.00.Found (percent): C, 70.06; H, 4.84; (21, 13.25.

EXAMPLE 10 10-chloro-4a/3-ethyl-7-methoxy-2,4a-dihydrophenanthren-Z-oneTo a solution of 360 mg. of 10-chloro-4afl-ethy1-7-methoxy 2,3,4,4atetrahydrophenanthren-Z-one in 15 ml. of t-butanol are added 0.27 ml. ofanhydrous pyridine and 167 mg. of selenium dioxide and the solution isrefluxed for hours under nitrogen atmosphere. After treating accordingto the same procedure as Example 9, the resulting oily residue ispurified through a column of alumina to yield 210 mg. of10-chloro-4afl-ethyl-7-methoxy-2,4a-dihydrophenanthren-Z-one having B.P.C./ 0.02 mm. Hg (bath temperature).

UV: A512? 232, 263.4 mg (3 18,700, 16,500). IR: .33 1665, 1630, 1604,1560, 1495, 1255 cm.-

Analysis-Calm. for C17H O2Cl (percent): C, 71.20; H, 5.27; Cl, 12.37.Found (percent): C, 71.43; H, 5.37; Cl, 12.11.

EXAMPLE 11 4afl-methyl-3(1,467-methylene-7-methoxy-2,3,4,4a,9,10-hexahydrophenanthren-Z-one UV: 15,335 230 m (e 16,100 IR: 93,2; 1678,1633,

An.':.lysis.Calcd. for (2 1 1 0 51, (percent): C, 72.32; H, 6.43; N,9.92. Found (percent): C, 72.29; H, 6.43; N, 10.22.

A solution of 700 mg. of this pyrazoline derivative and 2 ml. of 60%perchloric acid in 200 ml. of acetone is kept at room temperature for 10minutes. The reaction mixture is neutralized with 2 N-sodium carbonatesolution and then acetone is removed off. The product is extracted withdichloromethane, Washed with water, dried over anhydrous sodium sulfate,and evaporated to dryness to yield 581 mg. of residue, which oncrystallization from ether-pentane affords 456 mg. of4af3-methyl-3u,4a-methylene-7-methoxy 2,3,4, 4a,9,10hexahydrophenanthren- 2-one having M.P. 113.5114.5 C.

UV: 15, 25 229 mu 3 23,500 IR: 23 1671, 1613, 1575, 1503, 1286, 1272,1256, 1249, 1037, 954,873, 868 cm."

Analysis.Calcd. for C17H18O2 (percent): C, 80.28;

H, 7.13. Found (percent): C, 80.56; H, 7.15.

EXAMPLE 12 4a 3-ethyl-3a,4a-methylene-7-methoxy-2,3,4,4a,9,10-hexahydrophenanthren-2-one To a solution of diazomethane in ether,prepared from 17 g. of N-nitrosomethylurea, 49 ml. of 40% potassiumhydroxide solution, and 220 ml. of ether, is added a solution of 2.44 g.of -4a/3-ethyl-7-methoxy-2,4a,9,IO-tetrahydrophenanthren-2-one in 35 ml.of dichloromethane. The solution is kept overnight at room temperatureand then evaporated under reduced pressure to yield crude crystals,which on recrystallization from dichloromethane-ether afford 2.33 g. of4afi-ethy1-7-methoxy-3a,4a-(3',4',1'- pyrazolino) 2,3,4,4a,9,10hexahydrophenanthren-Z-one having M.P. 123124.5 C.

UV: 12,12? 230, 245, 327 mu (6 18,350, 14,390, 460). IR: vgg 1677, 1628,1612, 1244, 1039, 885 cm? Analysis.-Calcd. for C H O N (percent): C,72.95; H, 6.80; N, 9.45. Found (percent): C, 72.90; H, 6.93; N, 9.75.

A solution of 550 mg. of this pyrazoline derivative and 1.6 ml. of 60%perchloric acid in ml. of acetone is kept at room temperature for 15minutes. The reaction mixture is cooled with ice-pieces and neutralizedwith 2 N- sodium carbonate solution and then acetone is removed oft.Treatment as usual manner affords 547 mg. of residue, which oncrystallization from dichloromethane-ether affords 404 mg. of4a/3-ethyl-3a,4a niethylene-7-methoxy- 2,3,4,4a,9,'10hexahydrophenanthren-2-one having M.P. 102102.5 C.

UV: 1512 229, 278, 285 m (6 21,580, 2,170, 1,980 IR: 73 8:1672, 1613,1576, 1504, 1256, 1244, 1043, 909, 817 cm." Analysis.-Calcd. forC18H20O2 (percent): C, 80.56;

H, 7.51. Found (percent): C, 80.17; H, 7.47.

EXAMPLE 13 4aB-methyl-3u,4a-methylene-7-methoxy-2,3,4,4atetrahydrophenanthren-2-one To asolution of diazomethane in ether, prepared from 7.9 g. ofN-nitrosomethylurea, 22 ml. of 40% potassium hydroxide solution, and 98ml. of ether, is added a solution of 840 mg. of4aB-methyl-7-methoxy-2,4adihydrophenanthren-Z-one in 12 ml. ofdichloromethane and the solution is kept at room temperature for 3hours. The product obtained by treatment according to the same procedureas the Example 11 is crystallized from dichloromethane-ether to alford805 mg. of 4a;8-methyl-7-methoxy- 311,401 (3,4,1' pyrazolino) 2,3,4,4atetrahydrophenanthren-Z-one having M.P. l41.5,l-43.5 C.

UV: A3,? 218, 248, 270, 332, 382 m;1(e 18,600, 12,100, 8,900, 12,100,8,600 IR: 9,219 1661, 1606, 1568, 1500, 1286, 1270, 1251, 1029, 889 cm.Analysis.-Calcd. for C17H16O2N3 (percent): C, 72.84;

H, 5.75; N, 9.99. Found (percent): C, 72.67; H, 5.74;

A solution of 630 mg. of this pyrazoline derivative and 1.8 ml. of 60%perchloric acid in 180 ml. of acetone is kept at room temperature for 10minutes. The product obtained by treatment according to the sameprocedure as Example 11 is crystallized from ether-pentane andrecrystallized from dichloromethane-ether to yield 515 mg. of 4a,?methyl 351,461 methylene-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-onehaving M.P. 127.5-129 C.

UV: A223? 216, 247, 325 m (6 21,900, 15,600, 10,700). IR: .ggg 1664,1609, 1565, 1497, 1286, 1273, 1259, 1037, 883 cm." Analysis.-Calcd. forC H O (percent): C, 80.92;

H, 6.39. Found (percent): C, 80.79; H, 6.26.

EXAMPLE 14 4a-fl-ethyl-3a,4a-methylene-7-methoxy-2,3,4,4a-

tetrahydrophenanthren-Z-one To a solution of diazomethane in ether,prepared from 24 g. of N-nitrosornethylurea, 68 ml. of 40% potassiumhydroxide solution, and 310 ml. of ether, is added a solution of 2.57 g.of 4ap-ethy1-7-methoxy-2,4a,8-dihydrophenanthren-Z-one in 37 ml. ofdichloromethane and the solution is kept at room temperature for 3hours. Treatment according to the same procedure as the Example 11affords crude crystals, which on recrystallization fromdichloromethane-ether afford 3.20 g. of4a/3-ethyl-7-methoxy-3a,4a-(3,4',1-pyrazolino) 2,3,4,4atetrahydrophenanthren-Z-one having M.P. 172-175 C. (decomposition).

UV: ABS? 219.6 248.2, 270.9, 333, 384.5 m (6 18,400, 11,900, 9,200,11,700, 8,200)

Analysis.-Ca1cd. for C H O N (percent): C, 73.45; H, 6.16; N, 9.52.Found (percent): C, 73.09; H, 6.09; N, 9.65.

A solution of 2.70 g. of this pyrazoline derivative and 4.5 m1. of 60%perchloric acid in 450 m1. of acetone is kept at room temperature for 10minutes. The crude crystals obtained by treatment according to the sameprocedure as Example 11 are recrystallized from dichloromethane-ether toafford 20.2 g. of 4afi-ethyl-3a,4a-meth ylene-7uneth0xy 2,3,4,4atetrahydrophenanthren-Z-one having M.P. 9393.5 C.

UV: 15133 235 m 6 22,000). IR: .33; 1670, 1638,

Analysis.Calcd. for C H O (percent): C, 79.97; H, 6.71. Found (percent):C, 79.85; H, 6.79.

EXAMPLE 15 10-chloro-4afl-methyl-3 u,4a-methylene-7-methoxy-2,3,4,4a-tetrahydrophenanthren-2-one To a solution of 550 mg. of10-chloro-4afi-methyl-7- methoxy-2,4a-dihydrophenanthren-2-one in 3.5m1. of dichloromethane is added 13 ml. of the diazomethaneether solutionprepared from 2.0 g. of N-nitrosomethylurea according to the sameprocedure as Example 11 and the solution is kept at room temperature for1 hour. The product obtained by treatment as usual manner iscrystallized from ether to afford 535 mg. of l0-chloro-4aB- methyl 7methoxy-3u,4a-(3',4', -pyrazolino)-2,3,4,4atetrahydrophenanthren-Z-onehaving M.P. 183-185 C.

UV: A312? 221, 249.5, 273.5, 339, 389 m (6 21,320, 12,650, 9,800,11,1000, 7,670 IR: 5,259 1668, 1603, 1563, 1499, 1318, 898 cm.-

-Analysis.Calcd. for C H 'O N Cl (percent): C, 64.86; H, 4.80; N, 8.90;Cl, 11.26. Found (percent): C, 64.54; H, 4.82; N, 8.87; CI, 11.72.

A solution of 998 mg. of this pyrazoline derivative and 2.4 ml. of 60%perchloric acid in 240 ml. of acetone is kept at room temperature for 10minutes. The product obtained by treatment according to the sameprocedure as Example 11 is crystallized from ether to yield 711 mg. of10-chloro-4aB-methyl-36t,4a-methylene 7 methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one having M.P. 145- 146 C.

UV: 51:12, 218, 249.5, 268, 332, 370 m (6 25,710, 17,370, 12,600,10,710, 6,920). IR: .53; 1670, 1607, 1565, 1500, 1265, 1258 emfAnalysis.-Ca1cd. for C H O Cl (percent): C, 71.20; H, 5.27; Cl, 12.37.Found (percent): C, 70.64; H, 5.19; Cl, 12.92.

EXAMPLE 16 10-chloro-4afl-ethyl-3u,4a-methylene-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one To a solution of diazomethane inether, prepared from 3.4 g. of N-nitrosomethylurea, 9.1 ml. of 40%potassium hydroxide solution, and 42 ml. of ether, is added a solutionof mg. of 10-chloro-4a 8-ethyl-7-methoxy- 2,4a-dihydrophenanthren-2-ouein 2 ml. of dichloromethane and the solution is kept at room temperaturefor 2% hours. The product obtained by treatment according to the sameprocedure as Example 11 is crystallized from dichloromethane-ether toyield 118 mg. of 10-ch1oro- 455 ethyl 7 methoxy-3a,4u (3,4',1'pyrazoline)- 2,3,4,4a-tetrahydrophenanthren-2-one having M.P. 167- 168.5C.

UV: 15, 99 222, 253, 274, 338, 392 m). (6 18,100, 11,600, 10,100,10,600, 7,200). IR: vgg f 1669, 1603, 1563,

Analysis.Calcd. for C H O N C1 (percent): C, 65.75; H, 5.21; N, 8.52;Cl, 10.78. Found (percent): C, 65.58; H, 5.00; N, 8.40; Cl, 11.01.

A solution of 250 mg. of this pyrazoline derivative and 0.7 ml. of 60%perchloric acid in 70 ml. of acetone is kept at room temperature for 10minutes. The product obtained by treatment as usual manner iscrystallized 15 16 from ether-pentane to yield 199 mg. of10-chloro-4a/3- chloro 4afi methyl-7-methoxy 2,3,4,4atetrahydroethyl-3a,4a-methylene-7-methoxy 2,3,4,4atetrahydrophenanthren-Z-one.

phenanthren-Z-one having M.P. 131-133" C. 5. A compocnd according toclaim 1, namely 10- UV: 1 E12 218, 251, 268, 332, 370 m (e 23,600,15,400 chloro 421B -cthyl 7-methoxy-2,3,4,4a-tetrahydrophen- 12,1009,360, 6,130) 5 anthrenz'one- 6. A compound according to claim 1, namelyIO-chlo- A"alyslS- Ca1cdfor lfl l' z (Percent): c, 71-87;ro-4afi-methyl-7-methoxy-2,4a-dihydrophenanthren-Z-one. H, Cl, 11.79.Found (Percent): C, H, 7 A compound according to claim 1 namely 10-chloro 4afi ethyl-7-methoxy-2,4a-dihydrophenanthren- We claim: 0 -2-one.

1. A compound of the following structural formula A compound accordingto l i 1 namely 10 fiuoro 4aBethyl-7-methoXy-2,3,4,4a-tetrahydrophenanthren-Z-one.

9. A compound according to claim 1, namely 10- R 15 fluoro 4a,Bmethyl-7-methoxy 2,4a dihydrophenan- \i/ thren-Z-one.

i 10. A compound according to claim 1, namely 10- fluoro 421B ethyl 7methoxy 2,4a dihydrophenanthren-2-one. X References Cited UNITED STATESPATENTS wherein R and R each is lower alkyl, X is a member 3,683,0918/1972 Nagata et a1 260-586 H selected from the group consisting of ahydrogen atom and a halogen atom, and YZ is a member selected from ERREFERENCES the group consisting of Kuehne, J. Am. Chem. Soc. 83, 1492,1494 (1961),

2 2 and -Fet1zon et al., Chem. Abstracts 52, 2828b (1958).

Shionogi, Chem. Abstracts 70, 37556g (1969). 2. A compound according toclaim 1, namely 4a B-methyl-7-methoxy-2,3,4,4a-tetrahydrophenanthren-2-one. DANIEL HORWITZ,Primary Examiner 3. A compound according to claim 1, namely 4a}9- Us CLethy1-7-methoxy-2,3,4,4a-tetrahydrophenanthren-Z-one.

4. A compound according to claim 1, namely 10- 260-34851, 3485103101);424-3331

